One of the endogenous factors that modulate vascular tone is the endothelium-derived relaxing factor (EDRF) that is released from the endothelium in the arteries.
It has been shown that several endogenous agents relax vessels only in the presence of an intact endothelium (Furchgott et al, J. Cardiovas. Pharmacol. 6, 336 (1984)) and that this action is mediated by the release of EDRF from the intact endothelium. Acetylcholine is one of these endogenous agents.
There is reason to believe that the EDRF-mediated relaxation of vascular smooth muscle is impaired by hypercholesterolemia and/or atherosclerosis. Thus, cholesterol feeding has been shown to augment vascular contraction to various agents both in vivo (Kawachi et al, "Selective hypercontraction caused by ergonovine in the canine coronary artery under conditions of induced atherosclerosis," Circulation 69:441-450, 1984, Heistad et al, "Augmented responses to vasoconstrictor stimuli in hypercholesterolemic and atherosclerotic monkeys," Circulation Res. 54:711-718, 1984) and in vitro (Henry, P.D. et al "Supersensitivity of atherosclerotic rabbit aorta to ergonovine mediated by a serotonergic mechanism," J. Clin. Inverst. 66:306-313, 1980). Hypercholesterolemia has been shown to blunt the vasorelaxant effect of acetylcholine in iliac rings from cholesterol-fed monkeys (Freiman, P.C. et al, "Atherosclerosis impairs endothelium-dependent vascular relaxation to acetylcholine and thrombin in primates," Circulation Res. 58:783-789, 1986; Harrison, D.G. et al, "Restoration of endothelium-dependent relaxation by dietary treatment of atherosclerosis," J. Clin. Invest. 80:;808-1811, 1987. Furthermore, coronary vessels of patients with atherosclerosis are more subject to vasospasm, particularly in the areas of stenosis (Maseri, A. et al, "Coronary vasospasm as a possible cause of myocardial infarction, a conclusion derived from the study of preinfarction angina," N. Engl. J. Med. 299:1271-1277, 1978), notwithstanding EDRF. Ischemia will occur as a consequence of vascular vasospasm. The effect is of particular importance in the coronary vascular bed that supplies blood to the myocardium.
It is also known that blood vessels of animals with atherosclerosis do not relax well even if acetylcholine is administered even though the blood vessels relax to other stimuli like calcium antagonists.
Captopril has recently been shown to enhance endothelium dependent relaxation of "normal" rat aortic rings in vitro (Hartich, L.P. et al, "Effects of antihypertensive agents on vascular responses," Kidney Int. 35:326, 1989, Shultz, P. et al, "Effect of oral administration of antihypertensive agents on endothelium dependent and endothelium independent vascular relaxation," J. Am. Coll. Cardiol. 13:83A, 1989).
European Patent Application 0219782 to Scholkens discloses the treatment of atherosclerosis, thrombosis and/or peripheral vascular disease in mammals using an angiotensin converting enzyme (ACE) inhibitor or its physiologically tolerable salts. It further discloses that because ACE is predominantly localized in the luminal plasma membrane of the endothelial cell, ACE inhibitors can interfere in platelet-endothelium interaction. In addition, Scholkens discloses that ACE inhibition potentiates the action of bradykinin (a strong stimulator of prostacyclin release from endothelial cells) by inhibiting its degradation and ACE inhibitors, consequently, have an inhibitory effect on platelet aggregation.
G. de Nucci et al, "Effect of captopril on the bradykinin-induced release of prostacyclin from guinea pig lungs and bovine aortic endothelial cells," Br. J. Pharmacol., 95(3), 783-8, Nov. 1988, discloses that in bovine aortic endothelial cells shown on microcarrier beads, captopril (10 mu.K) did not affect the release of prostacyclin or of endothelium-derived relaxing factor (EDRF) induced by bradykinin. They were also ineffective as releasers of EDRF from bovine aortic endothelial cells. Thus, activation of angiotensin-converting enzyme is not involved.
B. Schoelkens et al, "Local Inhibition of Angiotensin II Formation and Bradykinin Degradation in Isolated Hearts," Clin. Exp. Hypertens. A (10, No. 6, 1259-70, 1988) discloses that the interactions of ramipril (RP) and B-3816 (Hoechst) with angiotensin I (ARG-I), angiotensin II (ARG-II) and bradykinin (BK) were studied in isolated rat hearts. It was concluded that BK is involved in the local cardioprotective actions of RP, possibly via releasing PG12 and EDRF.
W. H. van Gilst et al, "The Coronary Vasodilatory Mechanism of SH-Containing Converting Enzyme Inhibitors: Potentiation of Endogenous Nitrate," Circulation (78, No. 4, Pt. 2, 221, 1988) discloses that the coronary vasodilatory mechanism of an SH-containing converting enzyme inhibitor (captopril) was studied in isolated rat heart. These results support the hypothesis that the SH-group of certain ACE inhibitors potentiates the effect of locally increased BK by synergism with endogenous nitrate (EDRF).
P. Thuermann et al, "Anti-Ischemic Efficacy of Enalapril in Patients with Coronary Heart Disease. A Randomized Placebo-Controlled Double-blind Study (Ger.)," Klin. Wochenschr. (66, Suppl. 13, 87, 1988) discloses that in a randomized, placebo-controlled, double-blind, crossover study, enalapril (EN) was shown to have an anti-ischemic effect in 12 angina patients due not only to a fall in the pre- and after-load but perhaps to dilatation of the coronary vessels resulting from the release of the endothelium-derived relaxing factor following bradykinin accumulation induced by inhibition of kininase II as well.
P. Schultz et al, supra, discloses that in hypertension (HPN) both endothelium dependent (EN-D) as well as independent (EN-I) responses to vascular relaxants are depressed. In rats, the authors investigated whether anti-HPN agents affect EN-D and/or EN-I responses to agonists of vascular relaxation. Oral captopril, enalapril and hydralazine differentially affected vascular relaxations in response to EN-D (ACh) and EN-1 (Na nitroprusside) agonists. Indomethacin did not prevent the effect of ACh while both pyrogallol and Hb did inhibit ACh-induced relaxations. Therepeutic efficacy of anti-HPN agents may be modified by their differential effects on EN-D and EN-I vasodilation.
T. F. Luscher et al,"Antihypertensive Treatment Normalizes Decreased Endothelium-Dependent Relaxations in Salt-Induced Hypertension of the Rat," Circulation (74, No. 4, Pt. 2, 286, 1986) discloses that in isolated aorta from hypertensive rats, endothelium-dependent relaxation induced by ACh, adenosine and thrombin, but not Na nitroprusside, was significantly decreased compared to normotensive rats. Responses were unaffected by indomethacin. P.o. hydralazine+reserpine+hydrochlorothiazide normalized relaxation responses and prevented the development of hypertension, whereas P.o. enalapril was ineffective.
G. de Nucci et al, "Pressor Effects of Circulating Endothelin are Limited by its Removal in the Pulmonary Circulation and by the release of Prostacyclin and Endothelium-Derived Relaxing Factor," Proc. Natl. Acad. Sci. U.S.A. (85, No. 24, 9797-800, 1988) discloses that in vitro, endothelin (EL) contracted rabbit veins and rat stomach, and did not aggregate rabbit or human platelets or prevent their aggregation. Infusion of EL through guinea pig or rat lungs release PG12 and TXA2. Guinea pig lungs removed the EL without being affected by captopril. EL dilated rat mesenteric veins via endothelium-derived relaxing factor (EDRF) release; at higher doses EL cause vasoconstriction.
Andrews, P. et al, "Reversal of Experimental Acute Cerebral Vasospasm by Angiotensin Converting Enzyme Inhibition", Stroke, Vol. 13, No. 4, July-Aug. 1982, p. 480-483 discloses that the angiotensin converting enzyme inhibitor teprotide (SQ 20,881) was studied for its effect on acute cerebral arteriospasm after subarachnoid hemorrhage as determined angiographically in the dog and was found to be effective. At page 482, it is also indicated that "Moreover, in a parallel series of experiments testing the effect of converting enzyme inhibition on the delayed established cerebral arteriospasm, we found that teprotide could reverse that spasm as well. Our preliminary experience with the injectable form of the converting enzyme inhibitor enalapril, (the diacid MK-422) in four dogs with established delayed cerebral arteriospasm, indicates that this agent is at least as effective as teprotide in restoring arterial width in these animals. (Unpublished data).'
'. . . It remains to be determined whether administration of a converting enzyme inhibitor in humans soon after the diagnosis of a subarachnoid hemorrhage can prevent or reverse cerebral arterial spasm, thus duplicating clinically the effects observed in the experimental animals with these compounds."
Gavras, H. et al, "Reversal of experimental delayed cerebral vasospasm by angiotensin-converting enzyme inhibition", J. Neurosurg. 55:884-888, 1981, demonstrated the partial or total release of delayed cerebral vasospasm of the basilar artery and its branches using the ACE inhibitor teprotide administered by injection.
Miyazaki, S. et al, "Relief from digital vasospasm by treatment with captopril and its complete inhibition by serine proteinase inhibitors in Raynaud's phenomenon," Brit. Med. J., Vol. 284, 30 Jan. 1982, discloses that captopril improved a patient's digital circulation.
Trubestein, G., et al, "Treatment of Raynaud's phenomenon with captopril", DMW 1984, 109 Jg., Nov. 22, p 857-860 disclose that 20 patients with primary or secondary Raynaud's phenomenon, in whom prior therapy had included alpha-receptor blockers and other vasoactive substances, were treated with captopril (Lopirin), with marked subjective improvement in 14 cases.
Rustin, M., et al, "The effect of captopril on cutaneous blood flow in patients with primary Raynaud's phenomenon", Brit. J. of Dermatology (1987) 117, p 751-758 disclose that in a placebo-controlled, double-blind cross-over study in 15 patients with Raynaud's phenomenon, p.o. captopril significantly improved cutaneous blood flow but had no effect on frequency or severity of attacks. However, the authors conclude that "a therapy which increases the cutaneous blood flow in these patients does not necessarily influence the triggering factors provoking vasospasm."
Tosi, S., et al, "Treatment of Raynaud's Phenomenon with Captopril", Drugs Exptl. Clin. Res. XIII(1) 37-42 (1987) disclose that captopril significantly decreased the frequency and the severity of ischemic attacks in patients with Raynaud's disease, but did not affect the attacks in patients with scleroderma.
Rustin, M., et al, "Chronic leg ulceration with livedoid vasculitis, and response to oral ketanserin", Brit. J. of Dermatology (1989) 120, 101-105 discloses that no benefit was observed following treatment of a patient suffering from Raynaud's phenomenon and chronic leg ulceration with captopril.
Coffman, J., "Symptomatic Therapy for Raynaud's Phenomenon", Drug Therapy/June, 1989, p. 95-104, discloses that " . . . captopril does not decrease the incidence or severity of peripheral vasospasm in such patients [that is patients with Raynaud's who have hypertension secondary to scleroderma], despite blood pressure control. Captopril cannot be recommended for the treatment of Raynaud's phenomenon in nonhypertensive patients until controlled studies are performed."
U.S. Pat. Nos. 4,046,889 and 4,105,776 to Ondetti et al disclose proline derivatives, including captopril, which are angiotensin converting enzyme (ACE) inhibitors useful for treating hypertension.
U.S. Pat. No. 4,337,201 to Petrillo discloses phosphinylalkanoyl substituted prolines, including fosinopril, which are ACE inhibitors useful for treating hypertension.
U.S. Pat. No. 4,374,829 discloses carboxyalkyl dipeptide derivatives, including enalapril, which are ACE inhibitors useful for treating hypertension.
U.S. Pat. No. 4,452,790 to Karanewsky et al discloses phosphonate substituted amino or imino acids and salts thereof and covers (S)-1-[6-amino-2-[[hydroxy(4-phenylbutyl)-phosphinyl]-oxy]-1-oxohexyl]-L-p roline (SQ 29,852, ceranapril). These compounds are ACE inhibitors useful in treating hypertension.
U.S. Pat. No. 4,316,906 to Ondetti et al discloses ether and thioether mercaptoacyl prolines which are ACE inhibitors useful in treating hypertension. This Ondetti et al patent covers zofenopril.
It has now been found that angiotensin converting enzyme inhibitors are capable of relaxing blood vessels impaired through atherosclerosis and/or hypercholesterolemia by rehabilitating the EDRF system.